1. Field of the Invention
The present invention relates generally to resolving 3-DAMP enantiomers.
2. Description of the Background Art
The compound d-oxyphene is an intermediate in the synthesis of .alpha.- d-propoxyphene, a narcotic which is recognized and accepted as possessing effective analgesic qualities in humans.
A typical prior art procedure for producing d-oxyphene starts with propiophenone, which is reacted with dimethylamine hydrochloride and formaldehyde to produce racemic 3-DAMP. The racemic 3-DAMP is treated with benzyl Grignard reagent to produce a second asymmetric center. This results in the production and .alpha.- and .beta.-oxyphene, which are produced as a diastereomeric pair of racemic mixtures with .alpha.-oxyphene as the major product. The desired .alpha.-oxyphene isomer then is resolved using traditional crystallization methods to remove the unwanted enantiomer and the .beta.-diastereomer using a resolving agent such as D-10-camphorsulfonic acid, since the .alpha.-oxyphene enantiomer cannot be used to make the narcotic .alpha.-d-propoxyphene analgesic. While .beta.-oxyphene can be used to produce the antitussive levopropoxyphene (.alpha.-1-propoxyphene), this is a minor product in comparison with .alpha.-d-propoxyphene.
Hungarian Patent Publication No. 173,204 (Jeno Korsi et al.) describes resolution of dl-3-DAMP using (+)-dibenzoyl-D-tartaric acid in acetone at 55.degree. C. to obtain the desired 1-3-DAMP for the production of .alpha.-d-oxyphene. In the initial reaction, less than half of the 3-DAMP is resolved from the acetone mother liquor solution. The mother liquor then is heated so as to remove half the volume, which racemizes the 3-DAMP part of the salt so as to resolve an additional small yield of less than 10% of the original 3-DAMP starting material. This is done a total of four times to obtain approximately 95% of the 3-DAMP starting material with an optical rotation of [.alpha.].sup.25 .sub.D =+50.degree.-60.degree. and a melting point of 113.degree.-134.degree. C. (water content variable).
There are several major drawbacks of the procedure described in the Hungarian patent. First of all, very dilute conditions are necessary to allow resolution of only relatively small amounts of the desired enantiomer in large quantities of acetone. The procedure requires repeated boil downs to obtain the ultimate yield, and impurities tend to build up in the mother liquor during the boil-downs. Furthermore, from the rotation and melting point data, it is evident that resolution is not complete.
There remains a need in the art for improved methods for resolving 3-DAMP.